Impact of Plasma Alpha-1-acid Glycoprotein Variability on Free Lopinavir Levels

血浆 α-1-酸性糖蛋白变异对游离洛匹那韦水平的影响

• 批准号: 7617890
• 负责人: Ighovwerha Ofotokun
• 金额: $ 12.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617890
• 关键词: AIDS clinical trial group; Accounting; Acids; Acute-Phase Proteins; Adherence; Affinity; Anti-Retroviral Agents; Antiviral Agents; Antiviral Response; Binding; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Count; Cells; Chi-Square Tests; Childhood; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Commit; Complex; Computer software; Concentration measurement; Confidence Intervals; Data; Development Plans; Dose; Drug Kinetics; Drug Monitoring; Ensure; Ethics; Exhibits; FDA approved; Fellowship; Fostering; Generations; Glycoproteins; Goals; HIV; HIV-1; Hand; Highly Active Antiretroviral Therapy; Immune; In Vitro; Individual; Inflammation; Inhibitory Concentration 50; Institution; Linear Models; Link; Literature; Lopinavir; Measurement; Measures; Mediating; Mentors; Methods; Metric; Modeling; Multi-Drug Resistance; Odds Ratio; Orosomucoid; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Plasma; Plasma Proteins; Predisposition; Probability; Protease Inhibitor; Protein Binding; Proteins; RNA; Reporting; Research; Research Design; Research Methodology; Residual state; Safety; Severity of illness; Shapes; Side; Sigmoid colon; Simulate; Source; Spearman Rank Correlation Coefficient; Study Subject; Testing; Therapeutic; Time; Toxic effect; Training; Treatment Failure; Variant; Viral; Virus; Weight; antiretroviral therapy; base; career; career development; chemotherapeutic agent; cohort; design; drug development; experience; falls; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; hazard; in vivo; internal control; medication compliance; oncology; pharmacokinetic model; pregnant; programs; reconstitution; response; restoration; viral resistance

DESCRIPTION (provided by applicant): This proposal is an integrated career development plan that includes training in clinical and antiretroviral (ARV) pharmacokinetic (PK) research methods. The goal is to enable the candidate to establish an independent research career focused on ARV clinical pharmacology. The didactic training component will expand on the MSc in Clinical Research program and the AIDS Clinical Trials Group training fellowship which the candidate recently completed. The candidate's mentors have been involved in mentoring the candidate over the past two years and are committed to fostering his career development. The chief clinical conundrum of ARV therapy is that toxicity is often due to higher circulating drug concentrations, while viral resistance and treatment failure are related to inadequate ARV exposure. The plasma free fraction of ARV is inversely related to protein binding. Protease inhibitors (PI) are bound primarily to cc-1-acid glycoprotein (AAG), an acute phase protein whose plasma levels vary with HIV disease severity and in the setting of inflammation. As a result of this variability, and because of the high binding affinity and low saturation capacity of AAG, this protein has been shown to modulate the disposition and the therapeutic outcomes of chemotherapeutics agents used in oncology. It is therefore conceivable that changes in AAG levels could have similar effects on the PK and pharmacodynamic (PD) of the PIs. We hypothesize that plasma AAG levels in ARV-treated HIV-infected subjects decrease over time due to virologic suppression and immune reconstitution; and that changes in plasma AAG levels are inversely correlated with free concentrations of lopinavir (LPV). Changes in plasma AAG levels over time following institution of LPV/r based therapy will be measured, and correlated with changes in free LPV PK profile from baseline to week-16. Plasma AAG and LPV free levels will be measured by a fixed-time nephelometric method and HPLC-MS/MS respectively. The mean changes in AAG level from baseline to week-16 will be estimated and compared overtime using repeated-measures analyses. The correlation between week-16 changes in AAG levels and week-16 changes in free LPV PK profile following ARV therapy will be evaluated using a Pearson product moment correlation coefficient and the Spearman rank correlation coefficient. Since the free fraction of drug in plasma more accurately reflects the drug available to the target cell, and as a result its PD activities, the finding of an inverse relationship between plasma AAG levels and free LPV concentrations could have important implication in HIV pharmacotherapy.

描述（由申请人提供）：该提案是一项综合职业发展计划，包括临床和抗逆转录病毒（ARV）药代动力学（PK）研究方法的培训。目标是使候选人能够建立专注于抗逆转录病毒临床药理学的独立研究生涯。教学培训部分将扩展临床研究理学硕士项目和候选人最近完成的艾滋病临床试验小组培训奖学金。候选人的导师在过去两年中一直参与指导候选人，并致力于促进他的职业发展。抗逆转录病毒疗法的主要临床难题是，毒性通常是由于较高的循环药物浓度造成的，而病毒耐药性和治疗失败则与抗逆转录病毒药物暴露不足有关。抗病毒药物的血浆游离分数与蛋白质结合成反比。蛋白酶抑制剂 (PI) 主要与 cc-1-酸性糖蛋白 (AAG) 结合，这是一种急性期蛋白，其血浆水平随 HIV 疾病严重程度和炎症情况而变化。由于这种变异性，并且由于 AAG 的高结合亲和力和低饱和能力，该蛋白质已被证明可以调节肿瘤学中使用的化疗药物的处置和治疗结果。因此可以想象，AAG 水平的变化可能对 PI 的 PK 和药效 (PD) 产生类似的影响。我们假设，由于病毒学抑制和免疫重建，接受 ARV 治疗的 HIV 感染者血浆 AAG 水平随着时间的推移而降低；血浆 AAG 水平的变化与洛匹那韦 (LPV) 的游离浓度呈负相关。将测量基于 LPV/r 的治疗后血浆 AAG 水平随时间的变化，并将其与从基线到第 16 周的游离 LPV PK 谱的变化相关联。血浆中 AAG 和 LPV 游离水平将分别通过固定时间比浊法和 HPLC-MS/MS 进行测量。将使用重复测量分析来估计和比较 AAG 水平从基线到第 16 周的平均变化。 ARV 治疗后第 16 周 AAG 水平变化与第 16 周游离 LPV PK 曲线变化之间的相关性将使用 Pearson 乘积矩相关系数和 Spearman 等级相关系数进行评估。由于血浆中药物的游离分数更准确地反映了靶细胞可利用的药物及其 PD 活性，因此发现血浆 AAG 水平与游离 LPV 浓度之间的反比关系可能对 HIV 药物治疗具有重要意义。